The present invention is directed to the formulation of H2-receptor antagonists in liquid formulations.
Cimetidine is a histamine H2-antagonist which has been described in U.K. Patent Specification 1,397,436. Cimetidine has been shown to be useful in the treatment of duodenal, gastric, recurrent and stomal ulceration, and reflux oesophagitis and in the management of patients who are at high risk from haemorrhage of the upper gastrointestinal tract.
In the case of certain compounds which have bitterness problems and solubility characteristics, the provision of a dosage form which solves theses problems represents a considerable problem.
Many solutions to the problem of taste masking pharmaceutical compositions of cimetidine have been attempted. For example, cimetidine granules have been coated with various compositions such as ethylcellulose and polyvinyl and acrylic polymers. One such proposal is disclosed in U.S. Pat. No. 4,800,087 wherein a polymer mixture coating is employed. The mixture comprises a high temperature film forming copolymer of polymethyacrylic acid ester and acrylic acid ester and a low temperature film forming copolymers consisting of methacrylic acid ester and styrene acrylate. U.S. Pat. No. 4,892,740 discloses pharmaceutical preparations having improved flavouring characteristics obtained by the drug being coated by a polymeric substance which is soluble in gastric juice.
A non-aqueous, chewable composition for oral delivery of unpalatable drugs has also been attempted. In U.S. Pat. No. 5,597,844, Chauhan, Susil, the composition contains the drug intimately dispersed or dissolved in a pharmaceutically acceptable lipid that is solid at room temperatures. The composition also has a matrix that contains a granulating agent for the total composition and a rapid dispersal agent and optionally additives such as buffering agents, flavoring agents, surfactants and the like.
As noted, cimetidine has a pronounced bitter taste. This is not usually a problem when the dosage form employed is a capsule or a tablet designed to be swallowed, thereafter to disintegrate upon reaching the stomach. However, such dosage forms can be impractical when it is desired to administer a large amount of active ingredient, or to co-administer a relatively bulky second active ingredient such as an antacid or alginate. Moreover many individuals have difficulty in swallowing a solid dosage form. Consequently, a liquid dosage form is desirable but must be able to meet the taste and stability requirements necessary for formulation aspects.
It will be appreciated that a major requirement of such a dosage form is that they must be palatable, since an unpalatable formulation increases the risk of a patient neglecting to take a medicament. Such non-compliance with the dosing regimen will in turn delay or prevent the patient""s recovery from the condition under treatment.
A further requirement of such a composition is that once the formulation reaches the stomach, the individual particles, in a liquid dosage form such as a suspension, should release the active ingredient rapidly and completely in order to ensure that substantially all of the active ingredient is absorbed; that is to say the formulation should be bioavailable.
As noted, in the case of cimetidine, because of its bitterness, the provision of such dosage forms represents a considerable problem
There are four crystalline forms (hereinafter referred to as polymorphs) of the anhydrous base, and three polymorphs of the monohydrate of the base have been characterized. The anhydrous forms have been designated as polymorphs A-D while the hydrated forms have been designated polymorphs M1-M3.
EP-A-257823 describes a stable aqueous suspension of cimetidine wherein at least 90% of the cimetidine is in the polymorphic B form. It is disclosed that the use of polymorph B overcomes the problem of polymorphic interconversion found in the case of polymorph A suspensions of relatively low viscosity which tend to result in lumpy and non homogeneous suspensions.
EPA 0 138 540-A describes suspensions containing cimetidine and the preferred examples are buffered solutions of high viscosity. Because of the high viscosity, such suspensions are not easily poured from a bottle and consequently are usually formulated in sachets.
U.S. Pat. No. 4,996,222, Pharmaceutical formulations, Carlin et al. discloses a stable pharmaceutical composition suitable for oral administration comprising a suspension of an effective histamine H2-antagonist amount of particulate cimetidine in an aqueous phase wherein substantially all of the cimetidine present is of the polymorphic B form. However, this formulation also failed to achieve a stable composition which masked the taste of cimetidine.
Lastly, U.S. Pat. No. 4,786,735 discloses a process for preparing cimetidine polymorph B Graboyes, et al., comprising precipitating cimetidine from an aqueous-alcoholic solution of an acid addition salt.
It is generally recognized that substantially all formulations of cimetidine currently marketed contain polymorph A. Polymorph A can be prepared by recrystallizing cimetidine from a non aqueous organic solvent, particularly isopropanol, as described in GB No. 1,543,238. This process has been shown to be highly reproducible and to result in cimetidine which is easy to filter and has good bulk handling and formulation properties. A method of preparing another polymorph, polymorph D (sometimes referred to as polymorph Z), has also been disclosed in GB No. 2,108,117A.
In contrast to polymorphs A and D, polymorphs B and C are disclosed by Hegedus as being difficult to handle, due at least in part to their thixotropic properties in aqueous suspension which make separation by conventional methods such as filtration and centrifugation very difficult. This has also been the experience of the applicants up until the time of making the present invention
There still exists a need in this field for a liquid formulation of cimetidine which is stable, and taste masks the bitter taste of the product for use in a commercial setting.
The present invention is directed to a stable pharmaceuctical composition comprising cimetidine polymorph B, microcrystalline cellulose, carboxymethylcellulose, propylene glycol, and xanthan gum.
The present invention is directed to an unexpectently stable and good tasting liquid formulation of an H2 receptor antagonist. While many teaching abound in the art on how to make a tastemasked, or concealed formulation of an H2 receptor antagonist, the resulting liquid formulation have been commercially unacceptable. The formulations have failed on the basis of taste, and or on long-term stability.
For use herein the term histamine H2-antagonists shall mean cimetidine, ranitidine, famotidine, nizatidine, etinidine, lupitidine, nifentidine, niperotidine, roxatidine, sulfotidine, tuvatidine and zaltidine. Preferably the H2 antagonist is cimetidine, famotidine and ranitidine. More preferably it is cimetidine.
It is well known that for stability purposes in a liquid suspension formulation, the polymorph B form of cimetidine is necessary as the Polymorph A form will precipitate out in the formulation. The present invention utilizes the preferred polymorph form, polymorph B.
This invention relates to new pharmaceutical compositions and methods for their preparation, and in particular it relates to suspensions comprising cimetidine.
It is clear that there has been a need for compositions of cimetidine which are liquid based and are palatable. Cimetidine is absorbed almost exclusively in the small intestine and liquid-based compositions offer the possibility that they could be absorbed more quickly and more efficiently than tablet compositions, particularly tablet compositions which have been coated to minimise unpleasant tastes. However, with solutions of cimetidine, the unpleasant bitter taste is a particular problem. Suspensions of cimetidine could in principle offer the advantage of being more palatable but until recently no stable suspension compositions of cimetidine have been described or sold. Some companies have tried to meet the apparent need for such a product by selling cimetidine powder or granules in sachets which can be extemporaneously mixed with water to produce suspension compositions.
There is the difficulty of polymorphism which gives rise to problems of polymorphic transitions and crystal growth. It is generally recognised that cimetidine can exist in at least 5 different polymorphic forms and that these polymorphic forms differ in crystal habit and crystallisation properties, thermodynamic stability, and solubility and rate of dissolution in water. It is generally recognised that the polymorphic form A has been used almost exclusively in compositions. B. Hegedus and S. Gorog, J. Pharmaceutical and Biomedical Analysis, Vol. 3, No. 4, pp.303-313, 1985. It has now been found that the present invention produces a stable formulation of polymorph B in a suspension dosage form.
Aqueous suspensions of cimetidine polymorph A are thermodynamically unstable and it is found that when many such suspensions are prepared having relatively low viscosity, they are likely, when subjected to fluctuating temperatures, to undergo polymorphic transition into the polymorphic B form. This polymorphic transition, forms polymorph B in situ as very long needle-like crystals, which makes the suspensions lumpy and non-homogeneous thereby introducing dosage inaccuracy and giving rise to an unpleasant mouth feel.
It is an object of this invention to provide a suspension of cimetidine which is stable and, in particular, is of relatively low viscosity such that it can be easily poured from bottle and easily administered using a spoon or like device so that various dosages can be exactly and accurately measured. It is also an object of this invention to form a stable composition to which other ingredients such as antacids or alginates can be added.
We have now found that by preparing suspensions from cimetidine polymorph B, the problem of polymorphic transition and the growth in situ of long needle-like crystals can be avoided.
According to the invention, there is provided a stable pharmaceutical composition suitable for oral administration comprising a suspension of particulate cimetidine in an aqueous phase having a pH of about 6.8 to 8.8, preferably around 6 to 7, and a suspending agent, wherein substantially all of the cimetidine present is of the polymorphic B form, and optionally any other pharmaceutical excipients. The relatively high pH provides for a profile which prevents degredation.
Preferably at least 90% and particularly preferably at least 95% of the cimetidine is in the polymorphic B form. It is preferred that substantially no polymorph A is present.
By stable is meant a suspension which is capable of remaining in a pharmaceutically acceptable condition for a prolonged period, for example at least six months, preferably at least a year and most preferably for more than three years. Thus there should not be significant crystal growth, and any sediment formed should be capable of being re-suspended with only mild agitation, i.e. the sediment should not take the form of a xe2x80x9ccakexe2x80x9d or lumps which cannot readily be re-suspended. Preferably no sediment should form at all.
Examples of suitable suspending agents for use herein include xanthan gum, hydroxypropylmethylcellulose, methylcellulose, carageenan, sodium carboxymethyl cellulose, and sodium carboxymethyl cellulose/microcrystalline cellulose mixes, particularly sodium carboxymethyl cellulose/microcrystalline cellulose mixtures. Preferred suspending agents are thixotropic suspending agents such as xanthan gum, carageenan and sodium carboxymethyl cellulose/microcrystalline cellulose mixtures and mixtures thereof. More preferred suspending agents are microcrystalline cellulose blends, such as Avicel RC591, Avicel RC581 and Avicel CL611. Avicel is a trademark of FMC Corporation, and RC591, RC581 and CL611 are mixtures of microcrystalline cellulose and sodium carboxymethyl cellulose. Most preferred for use is a combination of predominately, Avicel CL611 and xanthan gums.
Microcrystalline cellulose is defined in the U.S. Pharmacopoeia National Formulary USP XXI (1985), page 1546, as being partially depolymerised cellulose obtained by treating fibrous plant material-derived alpha cellulose with mineral acids. As with the powdered cellulose, it is described as containing 97.0-102.0% of cellulose calculated on the dried basis.
The amount of suspending agent present will vary according to the particular suspending agent used and the presence or absence of other ingredients which have an ability to act as a suspending agent or which contribute significantly to the viscosity of the composition. In general, however, the amount of suspending agent will lie in the range 1-50% w/w relative to the cimetidine powder or granules.
Examples of suitable sweeteners to be used include bulk sweeteners such as sucrose, hydrogenated glucose syrup, the sugar alcohols sorbitol and xylitol, and sweetening agents such as sodium cyclamate, sodium saccharin, asparatame and ammonium glycyrrhizinate. Preferably a mixture is used, more preferably it is a mixture of sucrose and an artifical sweetner such as saccharin.
Particular examples of celluloses are microcrystalline celluloses such as Emcocel(trademark), (supplied by Edward Mendell of New York) and Avicel(trademark) (supplied by FMC Corporation of Philadelphia, Pa.). Particular grades of Avicel(trademark) include Avicel PH 103, Avicel PH 101 and Avicel PH 105. Further examples of celluloses are powdered celluloses such as Elcema(trademark) (supplied by Degussa of Frankfurt).
Additional excipients include, but are not limited to, flavouring agents, colourants, and preservatives, such as parabens.
Formulation Aspects
One formulation for cimetidine suspension (1%) is shown below.